Synthesis of Oxazoline and Oxazole Derivatives by Hypervalent- Iodine-Mediated Oxidative Cycloaddition Reactions

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2020, 52, 2299–2310 short review 2299 en

Syn thesis A. Yoshimura et al. Short Review

Akira Yoshimura*a‡ 0000-0002-2577-397X N N O Akio Saito*b‡ 0000-0002-8291-2059 Mekhman S. Yusubovc 0000-0001-9233-1824 Substrates R O R Oxazoline Isoxazoline a Viktor V. Zhdankin* 0000-0002-0315-8861 ArI(III) N N O

R O R a Department of Chemistry and Biochemistry, University of Oxazole Isoxazole Minnesota Duluth, Minnesota 55812, USA [email protected] [email protected] b Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-23-16 Naka-cho, Koganei, Tokyo 184-8588, Japan [email protected] c Research School of Chemistry and Applied Biomedical Scienc- es, The Tomsk Polytechnic University, 634050 Tomsk, Russian Federation

‡ Akira Yoshimura and Akio Saito contributed equally to this work.

Received: 08.03.2020 ring, such as oxazolines, oxazoles, isoxazolines, and isoxaz- Accepted after revision: 15.04.2020 oles, are particularly important in life-saving drugs, bioac- Published online: 18.05.2020 DOI: 10.1055/s-0040-1707122; Art ID: ss-2020-m0131-sr tive natural compounds, products of the pharmaceutical in- dustry, synthetic building blocks, and as metal catalyst li- Abstract Organohypervalent iodine reagents are widely used for the gands.10–12,14,16,24–29 Therefore, the reactions forming these preparation of various oxazolines, oxazoles, isoxazolines, and isoxazoles. heterocyclic rings and those introducing functional groups In the formation of these heterocyclic compounds, hypervalent iodine species can serve as the activating reagents for various substrates, as into these rings represent a hot topic, and numerous im- well as the heteroatom donor reagents. In recent research, both chemi- portant synthetic procedures based on these reactions have cal and electrochemical approaches toward generation of hypervalent been developed. The known procedures often have serious iodine species have been utilized. The in situ generated active species drawbacks, such as harsh reaction conditions, long reaction can react with appropriate substrates to give the corresponding heterocyclic products. In this short review, we summarize the hypervalent- times, limited substrate scope, or poor yields. In particular, numerous synthetic procedures utilizing metal reagents

iodine-mediated preparation of oxazolines, oxazoles, isoxazolines, and Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. isoxazoles starting from various substrates. have been developed for efficient and mild syntheses of ox- 1 Introduction azoline and oxazole derivatives.10–12,14,16,23–28,30 However, 2 Synthesis of Oxazolines some of the metal reagents are expensive, toxic, and rare; 3 Synthesis of Oxazoles 4 Synthesis of Isoxazolines therefore, new synthetic methodologies under metal-free 5 Synthesis of Isoxazoles and mild conditions have been extensively studied. 6 Conclusion Organohypervalent iodine compounds are known as non-toxic and environmentally friendly reagents that are Key words hypervalent iodine, oxidative cyclization, oxidative cyclo- utilized in many green and sustainable organic reactions.31– addition, oxazoles, oxazolines, isoxazoles, isoxazolines 33 The reactivity pattern of hypervalent iodine compounds is similar to that of transition-metal reagents.34–40 There- 1 Introduction fore, hypervalent iodine compounds have found wide application as efficient oxidative reagents and ligand transfer re- Heterocyclic structural blocks can be found in various agents in many reactions.41–49 In fact, numerous oxidative biologically active natural and non-natural products and reactions, benzyne-mediated reactions, and new bond- are widely employed in the synthesis of pharmaceuticals, forming reactions, such as carbon–carbon, carbon–hetero- agrochemicals, dyes, and polymeric materials.1–8 Numerous atom, or hetero–heteroatom bonds, have been accom- reviews and books on the synthesis and properties of het- plished using hypervalent iodine reagents under metal-free erocyclic compounds have been published.9–23 Five-mem- conditions. In particular, these reagents have been used for bered heterocycles with nitrogen and oxygen atoms in the various ring construction reactions. Numerous classes of heterocyclic compounds have been prepared under mild

Syn thesis A. Yoshimura et al. Short Review

oles 4 (Figure 1), starting from various substrates using hypervalent iodine species are summarized, and recent devel- opments in chemical and electrochemical synthetic procedures toward these heterocycles are discussed.

N N ON ON

R O R O R R 1 2 3 4 Oxazoline Oxazole Isoxazoline Isoxazole Akira Yoshimura (left) was born in Osaka (Japan) and completed his M.S. degree in 2007 and his Ph.D. in 2010, both from Tokushima Uni- Figure 1 Important azole derivatives versity, under the supervision of Professor Masahito Ochiai. During 2010–2015 he carried his postdoctoral research with Professor Viktor V. Zhdankin at the University of Minnesota Duluth. In 2016–2017 he 2 Synthesis of Oxazolines worked as a Visiting Research Assistant Professor at the Southern Meth- odist University (Dallas, USA). Since 2019 he has been a Researcher 5 at The oxazoline nucleus is present in many heterocyclic the University of Minnesota Duluth. His research interests are directed toward the synthetic and mechanistic organic chemistry of hypervalent compounds that have found important applications in me- main-group elements and heterocyclic chemistry. He has published dicinal and materials chemistry.14,51,53,54 Numerous synthet- over 60 research papers, mainly related to the chemistry of hypervalent ic strategies for the construction of the oxazoline ring have iodine and bromine. been explored. Particularly important are synthetic Akio Saito (second left) received his M.S. (1999) and Ph.D. (2003) de- approaches using hypervalent iodine reagents, such as (di- grees from the Tokyo University of Pharmacy and Life Sciences. In acetoxyiodo)arenes,55–65 iodosylarenes,66 (difluoroiodo)- 2001, he joined Professor Takeo Taguchi’s group as a research associate arenes,67 in situ generated iodine(III) species,68–73 or iodoni- at the same university. From 2005, he worked as an assistant professor 74,75 with Professor Yuji Hanzawa at the Showa Pharmaceutical University. In um ylides. This section covers synthetic methodologies 2012, he moved to his present position as an Associate Professor at the for the preparation of various oxazoline derivatives from Tokyo University of Agriculture and Technology. appropriate substrates using hypervalent iodine species. Mekhman S. Yusubov (second right) was born in Georgia. His M.S. The reactions of N-allylamides or N-propargylamides (1985), Ph.D. (1991), and Doctor of Chemical Sciences (1998) degrees with hypervalent iodine species results in an oxidative cy- were earned at Tomsk Polytechnic University in the laboratory of Pro- clization leading to oxazolines with various substituents. fessor Victor D. Filimonov. He is currently a professor at Tomsk Poly- For example, Harned’s group reported the oxidative cycliza- technic University. Since 1994 he has been involved in intense tion reaction of N-allylamides 5 using (diacetoxyiodo)ben- international collaborative research programs with leading research lab- oratories in South Korea, Germany, and the United Kingdom. In 2004 he zene in the presence of BF3·Et2O and acetic acid to give the started joint research in the area of hypervalent iodine chemistry with respective oxazoline compounds 6 in moderate to good Professor Viktor V. Zhdankin at the University of Minnesota Duluth. His yields (Scheme 1).55 The cyclization of chiral N-allylamides main research interests are in the fields of the chemistry of natural afforded the corresponding oxazolines in good yields and products and hypervalent iodine reagents. Professor Yusubov has pub- diastereoselectivities. lished over 100 scientific papers. Downloaded by: University of Minnesota - Twin Cities. Copyrighted material.

Viktor V. Zhdankin (right) was born in Ekaterinburg, Russian Federa- PhI(OAc)2 (1.2 equiv) O R2 BF ·Et O (1.2 equiv) OAc tion. His M.S. (1978), Ph.D. (1981), and Doctor of Chemical Sciences 3 2 O AcOH (10 equiv) (1986) degrees were earned at Moscow State University. He moved to 1 R N R1 R2 the University of Utah in 1990, where he worked for three years as an H CH2Cl2, rt, 2–5.5 h N 5 6 Instructor of Organic Chemistry and Senior Research Associate with 1 Professor Peter J. Stang. In 1993, he joined the faculty of the University R = Ph, 2-O2NC6H4, 4-MeOC6H4, Me, 24–85% of Minnesota Duluth, where he is currently a professor of chemistry. He t-Bu, (E)-PhCH=CH–, etc. has published about 300 research papers, has given over a hundred re- R2 = H, i-Pr search presentations in many countries, has edited several books, and Scheme 1 Oxidative cyclization of N-allylamides 5 co-authored the Handbook of Heterocyclic Chemistry (3rd Edition, 2010) with Professors A. R. Katritzky, C. A. Ramsden, and J. A. Joule, and authored a book on Hypervalent Iodine Chemistry (Wiley, 2013). His main A similar (diacetoxyiodo)benzene-mediated cyclization research interests are in the areas of synthetic and mechanistic organic of N-allylamides 7 in the presence of HF·Py, instead of chemistry of hypervalent main-group elements and organofluorine chemistry. In 2011 he received the National Award of the American BF3·Et2O and acetic acid, gave the respective acetoxymethyl- Chemical Society for Creative Research & Applications of Iodine Chemistry. containing oxazolines 8 in moderate to good yields (Scheme 2).61 Incidentally, when using substituted N-(E)-allylamides under the same conditions, the reaction resulted in endo- cyclization due to the carbocation stability to afford the ox- conditions using hypervalent iodine reagents.50–52 In the azine products instead of oxazolines. present review, synthetic approaches to the azole derivatives, oxazolines 1, oxazoles 2, isoxazolines 3, and isoxaz-

Syn thesis A. Yoshimura et al. Short Review

57 OAc azoline compounds 16 in good yields. This reaction proba- O R1 O R2 HF·Py (10 equiv) bly involved initial generation of acetyl hypoiodite (AcOI) N PhI(OAc)2 (2.5 equiv) N H R2 from (diacetoxyiodo)benzene and lithium iodide. Nagib and R1 NH CH2Cl2/THF (1:1) NH rt, 2 h co-workers reported the use of acetyl hypoiodite generated 3 O O R R3 from (diacetoxyiodo)benzene and elemental iodine in the 78 cyclization reaction of imidate compounds leading to the R1 = H, F; R2 = H, Cl 62–90% 3 65 R = Ph, 4-FC6H4, 4-MeOC6H4, Me, allyl, etc. respective oxazolines in good yields. The obtained prod- Scheme 2 Preparation of acetoxymethylated oxazolines 8 ucts could be converted into -amino alcohols by acidic hy- drolysis.

PhI(OAc) (1.1 equiv) I The reaction of N-allylamides 9 using (diacetoxy- O 2 O iodo)benzene and bis(tosylimide) gave 5-amino-oxazolines TMSI (1.1 equiv) R N CH2Cl2, rt, 24 h R N 10 in moderate to good yields (Scheme 3).60 The authors H 13 14 proposed that either PhI(OAc)(NTs ) or PhI(NTs ) was gen- 2 2 2 R = n-Pr, n-pentyl, t-Bu, c-C5H11, Ph, etc. 38–80% erated in situ from (diacetoxyiodo)benzene and bis- I PhI(OAc)2 (1.0 equiv) (tosylimide), and the generated active species reacted with O R2 R2 O LiI (1.0 equiv) R2 1 the olefin followed by intramolecular cyclization to produce R N CH Cl , rt, 12 h, N R1 H 2 2 2 N R2 the final oxazoline products. 15 16 1 R = Ph, 2-ClC6H4, 4-tol, 4-O2NC6H4, 3-pyridyl, 61–93% 2-furyl, 1-naphthyl, (E)-PhCH=CH, Bn, Cy, etc. O PhI(OAc)2 (1.5 equiv) NTs2 O 2 Ts2NH (2.0 equiv) R = H, Me R N R H ClCH2CH2Cl, 50 °C, 3 h N Scheme 5 Iodocyclization of N-allylamides and N-propargylamides 910

R = Ph, 3-BrC6H4, 4-FC6H4, 2-furyl, 42–80% 2-naphthyl, adamantyl, etc. Recently, synthetic procedures for the preparation of 5- Scheme 3 Preparation of 5-amino-oxazolines from N-allylamides 9 fluoromethyl-2-oxazolines from N-allylamides using in situ generated hypervalent iodine species in the presence of a Fu and co-workers reported the metal-free trifluoro- fluorine source have been developed. For example, Gilmour methylation of N-allylamides 11 by treatment with (diace- and co-workers reported the fluorocyclization reaction of toxyiodo)benzene and sodium trifluoromethanesulfinate N-allylamides 17 using 4-iodotoluene as a precatalyst and as the trifluoromethyl source (Scheme 4).58 The reaction Selectfluor as a terminal oxidant in the presence of mechanism probably involved formation of a free-radical amine/HF, producing the respective 5-fluoromethyl-2-ox- intermediate, which reacted with the alkenes to give the azolines 18 in moderate to good yields (Scheme 6).73 When

CF3-containing oxazolines 12 in moderate to good yields. the reaction of a chiral N-allylamide was performed under the same conditions, the desired oxazoline product was ob- 3 R tained in good yield and high diastereoselectivity. The au- Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. 1 3 PhI(OAc)2 (2.5 equiv) O R R CF3 CF3SO2Na (2.5 equiv) thors proposed that the mechanism of this catalytic reac- O R2 Ar N ClCH2CH2Cl, 40 or 90 °C 1 tion probably involved (difluoroiodo)toluene generation H Ar N R R2 24 or 72 h 11 12 from 4-iodotoluene, Selectfluor and the HF source. Another

1 2 R = H, Me; R = H, Me, Ph, 4-tol, 4-ClC6H4; 38–80% synthetic approach to 5-fluoromethyl-2-oxazolines from N- R3 = H, Me; Ar = Ph, 2-tol, 3-tol, 4-tol, 3-pyridyl, 2-furyl, etc. allylamides employed an electrochemical protocol. Very re- Scheme 4 Trifluoromethylation of N-allylamides 11 cently, Waldvogel and co-workers reported the generation

4-MeC6H4I (10 mol%) The combination of (diacetoxyiodo)benzene and Selectfluor (1.5 equiv) F O O trimethylsilyl iodide promotes intramolecular iodocycliza- amine/HF (1:4.5) R N R tion of N-allylamides 13 leading to the respective 5-iodo- H CH2Cl2, rt, 24 h N 17 18 methyl-2-oxazoline compounds 14 in good yields (Scheme R = Ph, 4-MeOC6H4, 2-BrC6H4, C6F5, 2-furyl, etc. 31–69% 5).56 Trimethylsilyl iodide serves as the iodine source and the activating reagent. When using trimethylsilyl bromide 4-MeC6H4I (1.0 equiv) O undivided cell F O or trimethylsilyl chloride as the halogen source, the respec- Pt II Pt, 3 F, 50 mA·cm–2 Ar N Ar tive 5-bromo- or 5-chloromethyl-2-oxazoline compounds H CH2Cl2/Et3N·5HF, N were also obtained in good yields. A similar iodocyclization 19 rt, 15 h 20 Ar = Ph, 4-tol, mesityl, 4-F CC H , 2-thienyl, etc. 18–68% reaction of N-propargylamides 15 using (diacetoxyio- 3 6 4 do)benzene with lithium iodide instead of trimethylsilyl Scheme 6 Preparation of 5-fluoromethyl-2-oxazolines using in situ iodide gave the corresponding (E)-5-iodomethylene-2-ox- generated hypervalent iodine species

Syn thesis A. Yoshimura et al. Short Review

of a hypervalent iodine species from stoichiometric Me amounts of 4-iodotoluene by electrochemical oxidation in 3,5-Cl2C6H3IO (1.5 equiv) O O F BF3·Et2O (2.0 equiv) the presence of Et3N·5HF. This active species promotes the R N CHCl3, rt, 10 min to 12 h R N oxidative cyclization of N-allylamides 19 to give the respec- H 25 26 tive 5-fluoromethyl-2-oxazolines 20 in moderate yields.71 R = Ph, 4-MeOC6H4, 4-ClC6H4, 2-furyl, Bn, n-C5H11, etc. 34–72% Moran and co-workers reported the catalytic hypervalent iodine species mediated oxidative cyclization of vari- R2 R2 R2 3,5-Cl2C6H3IO (1.5 equiv) F ous N-allylamides 21 or N-propargylamides 23 to give the 2 O R BF3·Et2O (2.0 equiv) O 1 respective oxazoline compounds 22 and 24 in moderate to R N CHCl3, rt, 5 min to 3 h R1 good yields (Scheme 7).68,69 The same group also reported H N 27 28 that when using -amidoketones as substrates oxazoline 1 R = Ph, 4-MeOC6H4, 4-ClC6H4, 2-furyl, Bn, n-C5H11, etc. 65–100% products were obtained in moderate to good yields. A R2 = Me, Et, Cy mechanistic investigation of the cyclization of N-allyl- Scheme 8 Preparation of ring-fused oxazoline compounds from amides with in situ generated hypervalent iodine reagents N-cyclohexenylamides by DFT calculations and kinetic experiments was reported. It was found that the rate-limiting step in this reaction was the substrate cyclization.70 Recently, a similar oxidative cy- Our group has also reported the cycloaddition reaction of clization of N-allylamides using electrochemically generat- carbodiimides 33 mediated by cyclic iodonium ylide 32 to ed hypervalent iodine species was developed by Francke give the corresponding ring-fused 4-oxazolines 34 in mod- and co-workers.72 erate to good yields.75

2-MeOC6H4I (20 mol%) 2 Me 1 R O O R Selectfluor (1–2 equiv) OH PhN C O (2 equiv) Me TFA (1.5 equiv) O Me – + 30 O Ar N 1 I MeCN, rt, overnight Ar N R O H 2 Me Ph CH2Cl2, rt, 4.5 d N R then 2 M NaOH O 21 22 O Ph 29 31 Ar = Ph, 4-MeOC6H4, 4-ClC6H4, 2-furyl, etc. 62–81% 44% R1 = H, Me; R2 = H, Me O Me 2-MeOC H I (20 mol%) O 6 4 2 O mCPBA (3.0 equiv) Ar RN C NR (1.5 equiv) Me O Me – + 33 O p-TsOH·H2O (3.0 equiv) I Ar1 N 1 Ar Me Ar Rh2(OAc)4 (5 mol%) N N H 2 MeCN, rt, overnight N Ar O or Cu(acac)2 (5 mol%) R O 23 24 R 32 PhCF3, rt or 60 °C 34 Ar1 = Ph, 4-ClC H , 4-MeOC H , 2-thienyl 50–82% 4 to 12 h 6 4 6 4 Ar = 2-n-PrOC H 25–88% 2 6 4 Ar = Ph, 4-ClC6H4, 2-PhC6H4, 4-tol, 2-naphthyl, 4-MeOC6H4 R = i-Pr, Cy, p-tol, TMS 2,6-(i-Pr) C H Scheme 7 Catalytic cyclization of N-allylamides 21 or N-propargyl- 2 6 3 amides 23 Scheme 9 Preparation of 4-oxazoline compounds from iodonium ylides Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. An efficient synthetic procedure for the preparation of bicyclic oxazoline compounds mediated by hypervalent io- 3 Synthesis of Oxazoles dine reagents has been developed. For example, Zhang and co-workers reported the reaction of N-cyclohexenylamides Oxazoles have found numerous applications in chemical

25 and 27 with an iodosylarene in the presence of BF3·Et2O and biomedical sciences, and many synthetic procedures to give the respective monofluorinated ring-fused oxazo- for oxazole ring formation from various precursors have lines 26 and 28 in moderate to excellent yields (Scheme been developed.10,16,28,30,51 Particularly important are meth- 66 8). BF3·Et2O served as the Lewis acid and also as a fluorine ods based on the use of hypervalent iodine reagents such as source in this reaction. The authors proposed that the (diacetoxyiodo)benzene,76–87 [bis(trifluoroacetoxy)iodo]- mechanism of the introduction of fluorine into products 26 benzene,79,88–91 iodosylbenzene,92–95 [hydroxy(tosyloxy)iodo]- and 28 involved initial formation of carbocationic interme- arenes,96–99 recyclable iodine(III) compounds,100 in situ gen- diates from the N-cyclohexenylamides. erated iodine(III) species,76,101–106 and iodonium ylides.107–113 In another example of the preparation of oxazoline The hypervalent-iodine(III)-mediated cyclization of N- compounds, an iodonium ylide was used for the construc- propargylamides represents a useful synthetic methodolo- tion of a bicyclic oxazoline (Scheme 9). Koser and co-work- gy for the construction of the oxazole nucleus. This meth- ers reported the preparation of ring-fused 4-oxazoline 31 odology is applicable to the synthesis of substituted oxaz- from cyclic iodonium ylide 29 and phenyl isocyanate (30).74 oles bearing nitrogen-containing groups,76 fluoride,101,102 iodide,95 or acetoxy groups.77 For example, the reaction of

Syn thesis A. Yoshimura et al. Short Review

N-propargylamides 35 with (diacetoxyiodo)benzene in the converted into the respective oxazole compounds 42 by io- presence of bis(sulfonyl)imides affords the respective oxaz- dine-mediated oxidative cyclization. oles 36 bearing sulfonamide groups in moderate to good Very recently, Nagib and co-workers reported the reac- yields (Scheme 10).76 The sulfonyl group in products 36 can tion of arylimidates 43 with (diacetoxyiodo)benzene in the be easily removed to give the respective amines. The reac- presence of cesium iodide under fluorescent light irradia- tion mechanism has been investigated by NMR spectrosco- tion leading to the corresponding oxazole products 44 in py using the deuterated alkyne variant of N-propargyl- moderate to good yields (Scheme 12).114 The key step in this amide. This cyclization reaction of N-propargylamides has reaction involved the double hydrogen atom transfer (HAT) also been accomplished using the in situ generated catalytic reaction by in situ generated radical species. The same hypervalent iodine species derived from iodobenzene and group has also achieved a one-pot procedure for the syn- Oxone. Similar oxidative cyclizations of N-propargylamides thesis of oxazoles from alcohols and nitriles. 37 were reported by Waldvogel and co-workers using electrochemically generated (difluoroiodo)arene, which gave Ar2 CsI (3 equiv) O O 102 PhI(OAc)2 (3 equiv) the fluorinated products 38 in moderate yields. 1 ν 1 2 Ar NH h , PhMe, 23 °C, 24 h Ar N Ar 43 44 (PhSO2)2NH (2.4 equiv) 1 O N(SO2Ph)2 Ar = Ph, 3-ClC6H4, 4-MeOC6H4, 1-naphthyl, etc. 49–99% PhI(OAc)2 (1.2 equiv) O 2 Ar = Ph, 2-tol, 2-ClC6H4, 2-pyridyl, 4-FC6H4, etc. R N CH2Cl2/HFIP (3:1) R N H rt, 8–12 h Scheme 12 Oxidative cyclization of arylimidates 35 36

R = Ph, 4-ClC6H4, 2-naphthyl, 2-thienyl, 44–77% BnCH2, t-Bu, etc. Du and co-workers reported the reaction of enamines

4-MeC6H4I (2.0 equiv) 45 with [bis(trifluoroacetoxy)iodo]benzene giving -triflu- O undivided cell F oroacetoxy enamines, which were further converted into 2- Pt II Pt, 3 F, 50 mA·cm–2 O R N R (trifluoromethyl)oxazoles 46 in moderate to good yields H CH2Cl2/Et3N·5HF N rt, 15 h (Scheme 13).91 The same group has also developed the acyl- 37 38 oxylation reaction of enamines using iodosylbenzene with R = Ph, 4-tol, 4-F3CC6H4, 2-thienyl, 20–65% (E)-PhCH=CH, etc. various carboxylic acids. The obtained -acyloxylated prod- Scheme 10 Preparation of oxazoles from N-propargylamides ucts can be further transformed into the corresponding oxazoles under acetic acid reflux conditions.92 Enamides have been converted into the corresponding 2 oxazole compounds using hypervalent iodine reagents un- H R2 R O der metal-free conditions.78,79,88–90 Nachtsheim and Hempel PhI(OCOCF3)2 (1.2 equiv) 1 1 R NH2 ClCH2CH2Cl, 45 °C F3C N R developed an efficient method for the oxidative cyclization 1.5–3 h 45 46 of N-styrylbenzamides 39 to give the corresponding oxaz- 1 R = Ph, 4-tol, 2-MeOC6H4, Me, t-Bu, etc. 49–99% 2 oles 40 using [bis(trifluoroacetoxy)iodo]benzene in the R = CO2Me, CO2Bn, CO2Et, PhCO, etc.

90 Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. presence of TMSOTf (Scheme 11). The key active io- Scheme 13 Preparation of 2-(trifluoromethyl)oxazoles from enamines dine(III) species in this reaction, PhI(OTf)2, is probably generated from [bis(trifluoroacetoxy)iodo]benzene and TMSOTf. A one-pot synthesis of oxazoles 42 from N-acylamino acids The reaction of 3-hydroxybut-2-enimidates 47 with (di- 41 was reported by Boto and co-workers.80 In this reaction, acetoxyiodo)benzene in the presence of benzotriazole the enamide intermediates were initially formed from N- (BTA) as an additive affords the rearranged 2,4,5-trisubsti- acylamino acids 41 via decarboxylation and were further tuted oxazoles 48 in moderate to good yields (Scheme 14).81 The product structure was confirmed by X-ray crystallogra- Ph phy. This reaction proceeds via initial isoxazole formation O PIFA (1.2 equiv) TMSOTf (2.2 equiv) O Ph followed by ring opening and recyclization to produce oxaz- Ar N CH2Cl2/Et2O (1:1) Ar N H –78 to 0 °C, 10–15 min oles 48. 39 40 Ar = Ph, 4-ClC H , 4-MeOC H , 3-FC H , 27–77% 6 4 6 4 6 4 R2 3-pyridyl, etc. R1OC R2 OH PhI(OAc)2 (1.4 equiv) PhI(OAc) (2 equiv) BTA (30 mol%) O 2 Ph O PhCO2H (4 equiv) 1 O ArO NH CHCl3, rt, 1 h ArO N COR Ph ClCH2CH2Cl, 50 °C, 2 h R N 47 48 H then I2 (1 equiv) R N CO2H 80 °C, 18 h Ar = Ph, 4-FC6H4, 4-EtC6H4 41–75% 41 42 R1 = MeO, EtO, Me, Ph; R2 = Me, Et, i-Pr, Ph R = Ph, 4-BrC6H4, 2-furyl, (E)-PhCH=CH, 14–74% t-Bu, etc. Scheme 14 (Diacetoxyiodo)benzene-mediated oxidative rearrange- ment of 3-hydroxybut-2-enimidates Scheme 11 Oxidative cyclization of enamides and N-acylamino acids

Syn thesis A. Yoshimura et al. Short Review

Convenient practical approaches for the preparation of of products 53 were comparable to those of the stoichio- oxazoles from monocarbonyl substrates and nitrile solvents metric reaction. According to the deuterium labeling exper- as the nitrogen source in the presence of hypervalent iodine iments, this catalytic [2+2+1] cycloaddition involved only reagents have been reported by several alkenyliodonium intermediates. groups.86,87,93,96,97,100,103–105 Furthermore, the reaction of dicarbonyl compounds 49 using iodosylbenzene in the pres- i) PhIO (1.8 equiv) 2 TfOH or Tf2NH (1.5 equiv) R ence of bis(trifluoromethanesulfonyl)imide also proceeded R3CN, rt to 80 °C, 8 h O R1 R2 as an oxidative cycloaddition reaction to give the respective R3 R1 ii) PhI or 4-ClC6H4I (20 mol%) N 93 carbonyl-substituted oxazoles 50 (Scheme 15). The reac- 52 Tf2NH (1.5 equiv) 53 tion of carbonyl compounds with amides as the nitrogen mCPBA (1.5 equiv) i) 26–82% R3CN, rt 24 h ii) 24–81% source instead of nitrile afforded the respective oxazoles in 1 n n 98,99 R = Ph, BnCH2, -C6H13, -Pr moderate to good yields. R2 = H, Me, Ph, n-Pr, Br; R3 = Me, Et, Ph Scheme 17 Metal-free [2+2+1] oxidative cycloaddition reactions R1 1 2 PhIO (1.5 equiv) R R Tf NH (3–6 equiv) O 2 R2 3 O O R3CN, 80 °C, 2–167 h R N 4 Synthesis of Isoxazolines 49 50 O 1 2 1 2 R = Ph, Me; R = Ph, Me, OEt; R –R = (CH2)4 35–89% R3 = Me, Et, Ph The isoxazoline ring is present in many important heterocycles that are widely used in several areas of chemistry Scheme 15 Oxidative cycloaddition of dicarbonyl compounds with ni- 24–26,52 triles and biomedical sciences. Hypervalent iodine reagents such as (diacetoxyiodo)benzene,115–129 [hydroxy(tosyloxy)iodo]benzene,130,131 iodosylbenzene,132–135 [bis(trifluoro- Iodonium ylides and various nitriles can be converted acetoxy)iodo]benzene,136 (dichloroiodo)benzene,137 and into the corresponding oxazoles in moderate to good also in situ generated iodine(III) species,138–141 can be used yields.107–113 For example, dimedone-derived iodonium as efficient tools for construction of the isoxazoline ring. ylide 29, reacting with nitriles in the presence of a metal The hypervalent-iodine-mediated oxidative cycloaddi- catalyst, can be easily transformed into ring-fused oxazole tion of aldoximes with unsaturated substrates represents a compounds bearing a monocarbonyl group 51 (Scheme powerful methodology for the synthesis of isoxazoline 16).108 The key nitrilium intermediates are probably gener- compounds.52,115–120,132–134,136,137 For example, the reactions ated from iodonium salts reacting with nitrile in the pres- of various aldoximes 54 with alkenes 55 and (diacetoxy- ence of the rhodium catalyst, followed by cyclization to iodo)benzene afford the corresponding isoxazolines 56 in form the respective ring-fused oxazoles. generally high yields (Scheme 18).116 The key intermediate in this reaction, nitrile oxide, is generated by oxidation of O Me the aldoxime with (diacetoxyiodo)benzene, and then the Me Me – + Rh2(OAc)4 (cat) O Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. I generated nitrile oxide reacts with alkenes to produce the RCN, reflux, 0.5–1 h Me Ph R N isoxazoline products. The reactions of disubstituted or tri- O 29 O 51 substituted alkenes with aldoximes using hypervalent io- R = Me, ClCH , Bn, Ph, p-tol 23–68% 2 dine reagents can proceed through oxidative cycloaddition Scheme 16 Rhodium-catalyzed cycloaddition of iodonium ylides with leading to the corresponding substituted isoxazolines.120,133 nitriles

R2 (1.1 equiv) The metal-free, regioselective hypervalent-iodine- 55 R2 PhI(OAc)2 (1.1 equiv), TFA (cat) mediated [2+2+1] cycloaddition reactions of alkynes, nitriles OH R1 N 1 O MeOH, rt R N and oxygen atoms leading to substituted oxazoles have 54 56 94,106 1 been developed. Reactions of alkynes 52 with iodosyl- R = Ph, BnCH2, n-Pr, 4-MeOC6H4, etc. 63–91% 2 benzene in nitrile solution in the presence of trifluoro- R = Ph, Br(CH2)4 methanesulfonic acid or bis(trifluoromethane)sulfonimide 94 gave the corresponding oxazole products 53 (Scheme 17). R2 (1.1 equiv) 58 Iodosylbenzene works in this reaction as the oxygen source R2 NH2OH·HCl (1 equiv), PhIO (1 equiv) NaOAc (1 equiv), SDS (10 mol%) and also as the activating reagent. Deuterium labeling ex- 1 R O R1 O periments indicate that alkenyliodonium and alkynyliodo- H2O, rt, 2.5–3 h N nium intermediates are initially formed from iodosylben- 57 59 1 81–92% R = Ph, i-Pr, 2-thienyl, 4-MeOC6H4, 3-O2NC6H4, etc. zene and alkynes. A catalytic version of this [2+2+1] cyc- 2 R = Ph, CO2Et, etc. loaddition was also reported.106 The oxygen source in the catalytic version of this reaction was mCPBA, and the yields Scheme 18 Iodine(III)-mediated preparation of isoxazolines

Syn thesis A. Yoshimura et al. Short Review

The treatment of aldoxime-bearing purine structures and co-workers.139,140 Our group has also performed the oxida- various alkenes with an iodine(III) reagent also leads to the tive cycloaddition of aldoximes 69 with maleimides 70 us- respective isoxazoline products in moderate to good ing catalytic hypervalent iodine species to give the corre- yields.136 A convenient one-pot synthesis of isoxazolines 59 sponding bicyclic isoxazoline compounds 71.141 The mecha- from aldehydes 57, hydroxylamine, and alkenes 58 using nism of this reaction involved initial formation of the active hypervalent iodine reagents also produces products 59 in hydroxy(aryl)iodonium species from 2-iodobenzoic acid good yields.132 This reaction involves initial formation of al- and mCPBA, followed by oxidative cycloaddition to give the doximes from aldehydes and hydroxylamine, followed by final products. Experimental evidence toward the interme- oxidative cycloaddition with alkenes to give the final prod- diate generation of hydroxy(aryl)iodonium species was ucts (Scheme 18). provided by 1H NMR spectroscopy and ESI-mass spectrom- Hypervalent-iodine-mediated oxidative cycloadditions etry. of aldoximes with cyclic alkenes has been used for the preparation of bicyclic isoxazoline compounds in moderate R2 (1.2 equiv) 67 to good yields.116,117,132 Likewise, the treatment of heterocy- R2 3,5-Me2C6H3I (20 mol%) Oxone (3 equiv) clic alkenes with various aldoximes using hypervalent io- 1 OH 1 O R N R N dine reagents affords the respective bicyclic isoxazoline MeOH/HFIP/H2O (10:10:1) 66 rt, 24 h 68 130 1 compounds. For example, the oxidative cycloaddition of R = Ph, 4-tol, 4-ClC6H4, n-Pr 17–99% 2 various aldoximes 60 with sultone 61 in the presence of R = Ph, 4-tol, Bn, n-C6H13, etc.

[hydroxy(tosyloxy)iodo]benzene proceeds smoothly to pro- R2 duce the corresponding products 62 (Scheme 19). A similar N O O 2 reaction using cyclic phospholene-oxide instead of sultone (5 equiv) R O N O resulted in the respective bicyclic products in moderate 70 1 OH 2-IC6H4CO2H (10 mol%) R N mCPBA (1.5 equiv), TfOH (1.2 equiv) yields. In addition, Yang and co-workers reported a practi- 1 O 69 R N cal procedure for the preparation of fulleroisoxazolines 65 CH2Cl2, rt, 24 h 71 1 from various aldoximes 63 and fullerene 64 using (diace- R = Ph, 4-tol, 4-ClC6H4, BnCH2, (E)-PhCH=CH, etc. 31–98% toxyiodo)benzene.121 This procedure can also be used for R2 = Me, H the synthesis of fulleropyrazolines from various hydrazones Scheme 20 Catalytic hypervalent-iodine-mediated oxidative cycload- and fullerene. dition of aldoximes with alkenes

OH (1 equiv) O R N O The intramolecular cyclization of aldoximes to produce 60 S O O fused isoxazolines was reported by several research O PhI(OH)OTs (1.1 equiv) S O groups.116,117,122–124,131 In the reaction of 2-(allyloxy)benzal- O THF, rt, 24 h R N 61 62 doximes 72 with [hydroxy(tosyloxy)iodo]benzene in water, (5 equiv) 30–87% R = Ph, BnCH2, 4-tol, an intramolecular cyclization of the aldoximes led to the

4-MeOC6H4, 2-naphthyl, etc. N tricyclic fused products 73 (Scheme 21).131 Das and co- Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. O R workers reported a similar intramolecular oxidative cycliza- OH (1 equiv) R N tion reaction of a furanose-based aldoxime using (diacet- 63 oxyiodo)benzene leading to furopyrano-2-isoxazoline PhI(OAc)2 (1 equiv) 123 toluene, rt, 90–170 min products in good yields. Sorensen and co-workers reported a tandem oxidative cyclization reaction forming a penta-

64 65 cyclic product 75 by the treatment of aldoxime 74 with (di- 124 R = Ph, 4-MeOC6H4, 4-tol, 15–51% acetoxyiodo)benzene. This reaction mechanism probably 2-furyl, 4-O NC H , etc. 2 6 4 involved initial formation of quinone derivatives from the Scheme 19 Oxidative cycloaddition of aldoximes with cyclic unsaturat- phenol moiety and nitrile oxide species, then followed by ed compounds cyclization of the quinone and nitrile oxide to give the desired pentacyclic compound. A catalytic, hypervalent-iodine-mediated oxidative cyc- Ciufolini and co-workers have reported the (diacetoxy- loaddition of aldoximes with various alkenes has been de- iodo)benzene-mediated generation of nitrile oxide species veloped by our group and others.138–141 For example, we from -oxo-oximes.125 The reaction of -oxo-ketoximes 76 demonstrated that a catalytic hypervalent iodine species, with norbornene (77) and (diacetoxyiodo)benzene in generated in situ from an iodoarene and Oxone, can pro- methanol gave the corresponding isoxazolines 78 in moder- mote the oxidative cycloaddition of aldoximes 66 with ate yields (Scheme 22). This reaction mechanism involved alkenes 67 to give the respective isoxazoline compounds 68 initial formation of the nitrile oxide from the -oxo-ket- (Scheme 20).138 A similar, catalytic hypervalent-iodine- oximes via ligand exchange and solvolysis, followed by the mediated synthesis of isoxazolines was reported by Yan and cycloaddition with the alkene to form the final products.

Syn thesis A. Yoshimura et al. Short Review

O R2 O 2 PhI(OH)OTs (1.1 equiv) R N OH H2O, rt, 45 min O 1 1 N R 72 R 73 1 R = H, 3,5-t-Bu2, 3-Cl, 3-Br, etc. 50–89% 2 R = Ph, Me, CH2OAc, H

HO HO N O O N H Me PhI(OAc)2 (2.2 equiv) Me OTBS OTBS HO TFE, rt, 1 h then 50 °C, 75 min O H H 74 75 73% Scheme 21 Hypervalent-iodine-promoted intramolecular cyclization of aldoximes

The reaction of ,′-dioxo-ketoximes 79 with norbornene disulfides 84, which produced the corresponding isoxazo- under the same conditions also gave the corresponding lines 85.129 A similar reaction using diselenides instead of isoxazoline compounds 80. disulfides afforded the selenium-containing isoxazolines in good yields. The authors suggested that this oxidative cy- O (CH2)3+nCO2Me PhI(OAc)2 (1.2 equiv) clization of allyl ketoximes proceeds via a radical mecha- N TFA (cat) OH + N nism. MeOH, rt, 0.5 h O n 76 77 78 n = 0 or 1 (1.2 equiv) 56–70% 5 Synthesis of Isoxazoles

O O COR PhI(OAc)2 (1.2 equiv) TFA (cat) Me R + N Isoxazoles belong to an important class of heteroaro- N MeOH, rt, overnight O 52 OH matic compounds with many practical applications. Hy- 79 77 80 R = Me, OEt (1.2 equiv) 52–77% pervalent iodine reagents such as (diacetoxyiodo)benzene,116,122,142–147 [bis(trifluoroacetoxy)iodo]benzene,136,148–151 Scheme 22 Oxidative cycloaddition of ketoximes with norbornene iodosylbenzene,134,135 [hydroxy(tosyloxy)iodo]benzene,152,153 and in situ generated iodine(III) species138,154 The oxidative cyclization of allyl ketoximes using (diacet- have been commonly used for isoxazole ring construction. oxyiodo)benzene can produce the corresponding isoxazo- Hypervalent-iodine-mediated oxidative cycloadditions lines bearing various functional groups.126–129 For example, of aldoximes with unsaturated substrates represents an ef- the reaction of allyl ketoximes 81 using (diacetoxy- ficient procedure for the construction of isoxazoles. For ex- iodo)benzene in the presence of HF·Py as the fluoride ample, the reaction of aldoximes 86 with terminal alkynes source gave the corresponding oxyfluorination compounds Downloaded by: University of Minnesota - Twin Cities. Copyrighted material. 82 (Scheme 23).128 The obtained isoxazolines 82 can be R2 converted into the monofluoromethyl-substituted -hy- PhI(OCOCF3)2 (1.5 equiv) OH 2 R1 N + R 1 O droxy ketones via a ring-opening reaction. Cai and Yu MeOH, rt, 7 h R N reported a (diacetoxyiodo)benzene-induced oxidative 86 87 88 (1.5 equiv) 10–94% 1 cycloaddition of allyl ketoximes 83 in the presence of R = Ph, n-Pr, (E)-PhCH=CH, 4-MeOC6H4, c-C6H11, etc. 2 R = Ph, 2-pyridyl, (CH2)4OH, etc. OH 2 R R N R PhI(OAc)2 (1.2 equiv) ON 2 R PhI(OAc)2 (1.2 equiv) HF·Py (10 equiv) 1 1 R OH + R R O R CH F N CH2Cl2/toluene (1:1) 2 MeCN/H2O (2:1), 0 °C, N 3 3 R –20 °C, 2 h R 90 10 min 81 82 89 (1.5 equiv) 91 R = CO2Me, CO2Et 63–83% S R2 42–86% R2 S 84 i) NaOAc (1.2 equiv) OH O N PhI(OAc)2 (1.5 equiv) ON NH2OH·HCl (1.2 equiv) O S 2 DBU (1.5 equiv) 1 R O MeOH, 60 °C, 1 h 1 R 1 + O R MeCN, rt, 6 h Ar O ii) PhI(OAc)2 (1.1 equiv) 83 85 O Ar2 rt, 1 h 2 O (1.3 equiv) 47–78% 92 93 1 O Ar Ar N 1 t R = Ph, -Bu, 4-FC6H4, 4-MeOC6H4 94 2 Ar1 = Ph, 4-tol, 4-BrC H , 4-FC H , 4-ClC H R = Ph, 4-tol, 4-ClC6H4, Me 6 4 6 4 6 4 2 81–92% Ar = Ph, 4-tol, 4-BrC6H4, 4-FC6H4, 4-ClC6H4, 2-furyl, 2-thienyl Scheme 23 (Diacetoxyiodo)benzene-mediated oxidative cyclizations of allyl ketoximes Scheme 24 Iodine(III)-mediated preparation of isoxazoles

Syn thesis A. Yoshimura et al. Short Review

R 3,5-Disubstituted oxazole compounds 97 can be pre- + – PhIO OH + R IPh OTf pared from the respective alkynyliodonium salts 96 and a t-Bu N t-Bu O CHCl3, rt N nitrile oxide generated from aldoxime 95 and iodosylben- 95 96 97 zene (Scheme 25).135 The mechanism of this reaction in- R = MeOCO, t-BuCO, 4-Ts, etc. 38–57% volves oxidative cycloaddition and loss of the iodonium Scheme 25 Cycloaddition of aldoxime 95 and alkynyliodonium salts 96 group. Very recently, our group reported the regioselective cycloaddition reaction of aldoximes with enaminones.153 The R2OC R3 O R3 reaction of aldoximes 98 with enaminones 99 and [hy- PhI(OH)OTs (2 equiv) OH + droxy(tosyloxy)iodo]benzene afforded the 3,4-disubstitut- R1 N R2 NMe R1 O 2 CH2Cl2, rt, 1.5–24 h N 98 99 100 ed isoxazoles 100 (Scheme 26). This reaction involves the (3 equiv) 34–98% regioselective cycloaddition of enaminones with the gener- 1 R = Ph, 4-tol, 4-ClC6H4, 2-naphthyl, BnCH2, etc. ated nitrile oxide followed by elimination of dialkylamine to R2 = Me, i-Pr, c-Pr, EtO, Ph R3 = H, Me produce 3,4-disubstituted isoxazole products 100. The reaction of -substituted enaminones under similar condi- Scheme 26 Regioselective cycloaddition of aldoximes with enaminones tions afforded the respective 3,4,5-trisubstituted isoxazoles in moderate yields. The hypervalent-iodine-mediated preparation of ring- 87, in the presence of [bis(trifluoroacetoxy)iodo]benzene, fused isoxazoles from aldoximes and cyclic alkynes has affords the corresponding 3,5-disubstituted isoxazoles 88 been reported.142,145,146,151 For example, the reaction of bicy- (Scheme 24).151 This reaction is also applicable for the syn- clo[6.1.0]nonyne 102 with various aldoximes 101 and thesis of isoxazole-derived nucleoside and peptide ana- [bis(trifluoroacetoxy)iodo]benzene gave the corresponding logues. The cycloaddition reaction of aldoximes and alkynes bicyclic 3,4,5-trisubstituted isoxazole compounds 103 in under similar conditions was used for the efficient prepara- good yields (Scheme 27). A one-pot synthesis of bicyclic tion of various types of isoxazole compounds. This reaction isoxazoles has been developed by Boons and co-workers.145 involves the initial generation of a nitrile oxide followed by The reaction of aldehydes 104 with hydroxylamine and cy- cycloaddition with the alkyne to form the isoxazoles. The clic alkyne 105 using (diacetoxyiodo)benzene gave isoxaz- reaction of internal alkynes 90 with 1-naphthyl aldoxime oles 106 in generally good yields. Another convenient one- 89 in the presence of a hypervalent iodine reagent gave the pot synthetic approach to bicyclic isoxazoles using phenolic respective 3,4,5-trisubstituted isoxazole compounds 91 in compounds (instead of cyclic alkynes) was reported by Liu moderate to good yields.136,144 A convenient one-pot syn- and co-workers.147 The reaction of aldoximes 107 with 2,3- thesis of flavone-derived isoxazoles 94 from aromatic alde- dimethylphenol (108) and (diacetoxyiodo)benzene gave the hydes 92, hydroxylamine and alkynes 93 using (diacetoxy- corresponding isoxazoles 109 (Scheme 27). In this reaction, iodo)benzene has also been reported (Scheme 24).143 the hypervalent iodine reagent serves as the oxidant for

both the aldoxime and the phenol. Downloaded by: University of Minnesota - Twin Cities. Copyrighted material.

R H H OH OH OH PhI(OCOCF3)2 (1.2 equiv) R N + N MeOH/H2O (1:1), rt, 2–5 min O H H 101 102 103 (1.2 equiv) 84–95% R = Ph, 4-MeOC6H4, C6F5, 4-O2NC6H4, etc. N R i) NaOH (1.5 equiv) O NH2OH·HCl (1.5 equiv) MeOH, rt, 2 h R O + ii) PhI(OAc)2 (2 equiv) 105 (1 equiv) 104 105 106 HO rt, 10 min HO R = Ph, 2-tol, BnCH2 (step ii) 51–90% OH OH R i) PhI(OAc)2 (2 equiv) Me Me MeCN/H O (2:1), rt 2 N OH + R N ii) PhI(OAc)2 (2 equiv) O Me Me 107 (2 equiv) OH 107 108 0 °C to rt then aq Na2S2O3 109 (step ii) (1.2 equiv) 32–91%

R = Ph, 4-MeOC6H4, EtOCO, 4-FC6H4, etc. Scheme 27 Iodine(III)-promoted preparation of bicyclic isoxazole compounds

Syn thesis A. Yoshimura et al. Short Review

R2 3,5-Me2C6H3I (20 mol%) Oxone (3 equiv) 1 OH + 2 R N R R1 O MeOH/HFIP/H2O (10:10:1) N 110 111 rt or 40 °C, 24 h 112 (1.2 equiv) 27–75% 1 R = Ph, 4-tol, 4-ClC6H4 2 R = Ph, 4-tol, 4-BrC6H4, n-C6H13 Me Me Me Me PhI (10 mol%) Me H mCPBA (1.1 equiv) N + MeO N OH R Me MeOH/HFIP/CH2Cl2 (10:10:1) O O O 114 rt, 12 h 113 115 R (1.2 equiv) 32–98%

Ar = Ph, 4-tol, 4-BrC6H4, CH2Br, etc. Scheme 28 Catalytic hypervalent-iodine-mediated preparation of isoxazoles from alkynes and aldoximes or ketoximes

Catalytic procedures for the hypervalent-iodine-medi- Funding Information ated synthesis of isoxazoles have been developed.138,154 For example, the reaction of aldoximes 110 with alkynes 111, This work was supported by a research grant from the Russian Sci- ence Foundation (RSF-16-13-10081-P), the Tomsk Polytechnic Uni- in the presence of an iodoarene and Oxone, affords the re- versity Competitiveness Enhancement Program and the National spective 3,5-isoxazole products 112 in low to good yields Science Foundation (CHE-1759798). A.S. is grateful to the Japan Soci- (Scheme 28).138 This reaction probably involves initial for- ety for the Promotion of Science (JSPS), Fund for the Promotion of mation of a nitrile oxide, which further reacts with the Joint International Research (Grant No. 16KK0199).Russian Science Foundation (RSF-16-13-10081-P)Tomsk Polytechnic University Competitiveness Enhancement Program ()National Science Foundation (CHE-1759798)Japan Society for the Promotion o fScience (16KK0199) alkyne to give the final isoxazole. Recently, Kaliappan and Subramanian reported the oxidation of a cyclic -ketoxime References to a nitrile oxide using an in situ generated hypervalent iodine species.154 The reaction of cyclic -ketoxime 113 and (1) Vargas, D. F.; Larghi, E. L.; Kaufman, T. S. Nat. Prod. Rep. 2019, 36, alkynes 114 with a catalytic amount of iodobenzene using 354. mCPBA in methanol solution afforded the corresponding (2) Miao, Y.-h.; Hu, Y.-h.; Yang, J.; Liu, T.; Sun, J.; Wang, X.-j. RSC Adv. isoxazole compounds 115 bearing a cyclopentyl group in 2019, 9, 27510. (3) Madawali, I. M.; Gaviraj, E. N.; Kalyane, N. V.; Shivakumar, B. low to excellent yields. The key intermediate in this reac- Am. J. PharmTech Res. 2019, 9, 256. tion, the nitrile oxide, is probably generated by iodine(III)- (4) Soor, H. S.; Appavoo, S. D.; Yudin, A. K. Bioorg. Med. Chem. 2018, mediated methanolysis of the -ketoxime, and then the re- 26, 2774. sulting nitrile oxide is converted into product 115 by oxida- (5) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi, tive cycloaddition with the alkyne. M.; Bawa, S. Eur. J. Med. Chem. 2015, 97, 871.

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Syn thesis A. Yoshimura et al. Short Review

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